This proposal outlines an integrated training and research plan Dr. Mingye Feng will complete during the award period. The overall objective of the research proposal is to understand the underlying mechanism of macrophage-mediated immunosurveillance in cancer development and metastasis. The ability to escape from surveillance by the immune system is regarded as one of the essential hallmarks of cancer cells. While the functions of lymphocytes (T, B and NK cells) in tumor immunosurveillance have been studied for decades, the roles of macrophages on tumor cell elimination have only begun to be explored. Recent studies showed that blockade of a don't eat me signal CD47 on malignant hematopoietic and various solid tumor cells enabled their phagocytosis by macrophages and prevented their engraftment in mice lacking T, B, and NK cells, indicating a key role of macrophages in tumor surveillance and elimination. While inducing macrophage- mediated immunosurveillance holds considerable promise for the treatment of various cancers, its underlying mechanism remains largely unknown. The proposed research will focus on two fundamental questions: how do macrophages target tumor cells and how do cancer cells develop multiple levels of self-protective mechanisms against macrophages during cancer progression and metastasis? In the research plan, specific aim1 is to understand the molecular mechanism of tumor cell recognition and phagocytosis. Aim1 will define how macrophages present the tumor cell detecting molecules on the cell surface and how these molecules mediate the recognition of target cancer cells. Specific aim2 is focused on the multiple layers of self-protective mechanisms against macrophages developed by cancer cells during the process of metastasis. In the K99 phase, aim1 will be mostly completed, and the in vitro and in vivo selection models will be generated for continued investigation towards aim2 in the R00 phase. The proposed studies should shed light on the basic mechanism of tumor cell immune evasion, and enable the development of novel anticancer therapies exploiting the tumoricidal role of macrophages. The training and research plan will be carried out in Dr. Irving L. Weissman's laboratory at Stanford University School of Medicine. The candidate's immediate career goal is to complete the training in the K99 phase to further improve his scientific knowledge and skills, including performing research, attending conferences and courses, writing grants, presenting research work and managing laboratory, which should prepare him for advancing to independence. The candidate's long-term goal is to become an independent principle investigator and perform research in cancer immunology. The candidate's training and research during the K99 phase will receive full support from Dr. Weissman, Stanford Institute for Stem Cell Biology and Regenerative Medicine, and Stanford School of Medicine, who will provide an outstanding environment to foster his career development towards an independent researcher.